Anti-tuberculosis constituents from the stem bark of Micromelum hirsutum

• Published in: Planta medica Vol. 71; no. 3; pp. 261 - 267
• Main Authors: Ma, C, Case, R.J, Wang, Y, Zhang, H.J, Tan. G.T, Nguyen Van Hung, Nguyen Manh Cuong, Franzblau, S.G, Soejarto, D.D, Fong, H.H.S
• Format: Journal Article
• Language: English
• Published: Germany 01.03.2005
• Subjects: alkaloids; Animals; antibacterial properties; Antitubercular Agents - administration & dosage; Antitubercular Agents - pharmacology; Antitubercular Agents - therapeutic use; carbazoles; chemical structure; cultured cells; cytotoxicity; Humans; lactones; macrophages; Macrophages - microbiology; Mice; Microbial Sensitivity Tests; micromeline; Micromelum; Micromelum hirsutum; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - pathogenicity; phytochemicals; Phytotherapy; Plant Bark; plant extracts; Plant Extracts - administration & dosage; Plant Extracts - pharmacology; Plant Extracts - therapeutic use; Rutaceae; spectral analysis; stereochemistry; tuberculosis; Vietnam
• ISSN: 0032-0943; 1439-0221
• DOI: 10.1055/s-2005-837826

Anti-TB bioassay-directed fractionation led to the isolation of six carbazole alkaloids, as well as the gamma-lactone derivative of oleic acid, from the CH (2)Cl (2) extract of the stem bark of Micromelum hirsutum. The carbazoles include the new micromeline ( 2) and five known alkaloids: lansine ( 3), 3-methylcarbazole ( 4), methyl carbazole-3-carboxylate ( 5), 3-formylcarbazole ( 6), and 3-formyl-6-methoxycarbazole ( 7). Compound 1 was identified as the lactone derivative of oleic acid, (-)- Z-9-octadecene-4-olide, for which the trivial name micromolide ( 1) is suggested. It showed potent in vitro anti-TB activity against H37R v (MIC: 1.5 microg/mL), a selectivity index (SI) of 63, and exhibited activity against the Erdman strain of M. tuberculosis in a J774 mouse macrophage model (EC (90) : 5.6 microg/mL). Thus, 1 appears worthy of further evaluation as a potential new anti-TB agent. Isolates 2, 3, 6 and 7 had anti-TB MIC values between 14.3 and 42.3 microg/mL, while compounds 4 and 5 were considered inactive (MIC > 128 microg/mL). Structure elucidation and identification were based on spectroscopic analysis, including MS, 1D/2D NMR, and a full (1)H spin system analysis of 1.